Prolonged microglial cell activation and lymphocyte infiltration following experimental herpes encephalitis.
Experimental murine herpes simplex virus (HSV)-1 brain infection stimulates microglial cell-driven proinflammatory chemokine production which precedes the presence of brain-infiltrating systemic immune cells. In the present study, we investigated the phenotypes and infiltration kinetics of leukocyte trafficking into HSV-infected murine brains. Using real-time bioluminescence imaging, the infiltration of luciferase-positive splenocytes, transferred via tail vein injection into the brains of HSV-infected animals, was followed over an 18-day time course. Flow cytometric analysis of brain-infiltrating leukocytes at 5, 8, 14, and 30 days postinfection (d.p.i.), was performed to assess their phenotype. A predominantly macrophage (CD45(high)CD11b(+)Ly6C(high)) and neutrophil (CD45(high)CD11b(+)Ly6G(+)) infiltration was seen early during infection, with elevated levels of TNF-alpha mRNA expression. By 14 d.p.i., the phenotypic profile shifted to a predominantly lymphocytic (CD45(high)CD3(+)) infiltrate. This lymphocyte infiltrate was detected until 30 d.p.i., when infectious virus could not be recovered, with CD8(+) and CD4(+) T cells present at a 3:1 ratio, respectively. This T lymphocyte infiltration paralleled increased IFN-gamma mRNA expression in the brain. Activation of resident microglia (CD45(int)CD11b(+)) was also detected until 30 d.p.i., as assessed by MHC class II expression. Activated microglial cells were further identified as the predominant source of IL-1beta. In addition, infected mice given primed immunocytes at 4 d.p.i. showed a significant increase in mortality. Taken together, these results demonstrate that intranasal infection results in early macrophage and neutrophil infiltration into the brain followed by prolonged microglial activation and T lymphocyte retention. Similar prolonged neuroimmune activation may contribute to the neuropathological sequelae observed in herpes encephalitis patients.
Marques
Cristina P
CP
Center for Infectious Diseases and Microbiology Translational Research, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Cheeran
Maxim C-J
MC
Palmquist
Joseph M
JM
Hu
Shuxian
S
Urban
Stina L
SL
Lokensgard
James R
JR
D000818:Animals; D001921:Brain / Q000276:immunology / Q000473:pathology; D002465:Cell Movement / Q000276:immunology*; D020803:Encephalitis, Herpes Simplex / Q000276:immunology / Q000473:pathology*; D005260:Female; D018259:Herpesvirus 1, Human / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D007700:Kinetics; D008264:Macrophages / Q000276:immunology / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D017628:Microglia / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D020556:Neutrophil Infiltration / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors
D007371:Interferon-gamma